Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.752450
Title: Electron paramagnetic resonance techniques for pharmaceutical characterization and drug design
Author: Vallotto, Claudio
ISNI:       0000 0004 7425 5807
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2017
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Thesis embargoed until 05 Apr 2020
Access from Institution:
Abstract:
This thesis aims to explore the applicability of Electron Paramagnetic Resonance (EPR) spectroscopy in the pharmaceutical field. EPR is a powerful biophysical tool that allows the detection and characterisation of paramagnetic species, such as free organic radicals and metal complexes. EPR is widely used across all disciplines but to date has been much underutilised in the pharmaceutical industry. In the first part of this work, EPR techniques were applied to characterise the degradation products originating from irradiation sterilization of two common excipients, L-histidine and D-mannitol. Radicalic degradants can form as a result of several degradation pathways and industrial processes, including γ-radiation sterilization. A quantification of the radical species formed upon γ-irradiation was performed, indicating a much higher radical concentration for D-mannitol compared to L-histidine at pharmaceutically relevant irradiation doses. Cold irradiation analysis allowed the study of the low temperature stable species and their evolution into the r.t. stable ones. Three low temperature persistent radical species of D-mannitol were identified for the first time. The reactivity of the radicals in solution was also investigated. Spin trapping experiments allowed trapping of radicals from both L-histidine and D-mannitol. An unusual, and potentially hazardous, radical regeneration mechanism was observed for L-histidine, which was suggested to be due to the sterile metal needles used for transferring the sample solution in the EPR tubes. The second part of this work was concerned with the investigation of the radicalic mechanism of action of a promising photo-activable platinum(IV) anticancer complex. It has been previously suggested that the cytotoxicity of the said compound is associated to the photo-release of azidyl radicals, which can be quenched in the presence of the amino acid L-tryptophan. By the use of the spin trapping methodology, an intermediate indole radical was isolated and identified from photo-activation of the anticancer complex in the presence of both L-tryptophan and melatonin. The same photo-protective effect was observed also in the presence of a tryptophan-containing peptide. Thus, this work contributed to the overall understanding on photo-irradiated platinum anticancer complexes and their generated photo-products.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.752450  DOI: Not available
Keywords: QD Chemistry
Share: